Rho associated protein kinases (ROCKs) are Ser/Thr protein kinases, activated by small GTPases of the Rho family that act as molecular switches to mediate cell signaling. The Rho/ROCK signaling pathway (Lu et al. 2009) is known to participate in the regulation of numerous cellular functions such as actin cytoskeleton organization, contraction, cell adhesion, motility, and morphology, proliferation, cytokinesis, gene expression, and angiogenesis.
Rho kinases are important drug targets involved in several therapeutic areas including cardiovascular diseases (Shimokawa et al. (2007); Xing et al. (2006); Liao et al. (2007); Shimokawa et al. (2005); Dong et al. (2009); Hu et al. (2005)), CNS disorders (Kubo et al. (2008); Kubo et al. (2007)), inflammation (LoGrasso et al. (2009)), and cancer (Suwa et al. (1998); Kamai et al. (2004); Schmitz et al. (2000); Imamura et al. (2000); Somlyo et al. (2000); Uchida et al. (2000); Itoh et al. (1999); Uehata et al. (1997); Ishizaki et al. (2000); Narumiya et al. (2000); Nakajima et al. (2003a); Nakajima et al. (2003b); Ying et al. (2006); Somlyo et al. (2003); Hampson et al. (2009); Igishi et al. (2003); Liu et al. (2009); Ogata et al. (2009); Zohrabian et al. (2009); Micuda et al. (2010)). Rho kinases and the effects of ROCK inhibitors upon several hallmarks of cancer, including invasion (Imamura et al. (2000); Somlyo et al. (2000)), metastasis (Itoh et al. (1999); Belgiovine et al. (2010)), proliferation and angiogenesis (Uchida et al. (2000); Nakabayashi et al. (2011); Yin et al. (2007)) have been reported.
Co-overexpression of Rho and ROCK proteins in cancer cells has been reported in ovarian cancer, pancreatic, testicular, and bladder cancer (Suwa et al. (1998); Kamai et al. (2004)). The Rho/ROCK pathway plays an important role in the development and progression of cancer by modulating the changes (required for malignant transformation and for the process of metastasis) in the migratory, invasive and adhesive properties of tumor cells, and changes in the regulation cellular processes depending on the proper assembly/disassembly of actin-cytoskeleton (Schmitz et al. (2000)). The involvement of the Rho/ROCK signalling pathway in tumor cell invasion, angiogenesis, and metastasis has been well documented. In light of these findings inhibition of ROCKs has been proposed as a promising strategy in the prevention of cell invasion, a central event in the process of metastasis (Itoh et al. (1999); Uehata et al. (1997); Ishizaki et al. (2000); Narumiya et al. (2000)).
The potential of ROCK inhibitors as anticancer drugs was demonstrated by the identification of ATP competitive inhibitors, Y27632, and Wf536 (FIG. 1) (Itoh et al. (1999); Nakajima et al. (2003a); Nakajima et al. (2003b); Somlyo et al. (2003)), displaying high inhibitory potency for ROCKs. Specifically, Y27632 was reported to reduce metastasis in animal model systems (Itoh et al. (1999)), while Wf-536 has shown efficacy in preventing tumor metastasis in vivo models by inhibiting tumor-induced angiogenesis as well as tumor motility (Nakajima et al. (2003a); Nakajima et al. (2003b); Somlyo et al. (2003)). Han and coworkers have also investigated the ability of Fasudil, currently the only ROCK inhibitor clinically approved (in Japan for the treatment of cerebral vasospasm) to inhibit tumor progression in human and rat tumor models (Ying et al. (2006)).